美国威斯康星大学Lu Qiongshi课题组在研究中取得进展。他们发现，基于父母阿尔茨海默病病史的代理全基因组关联研究普遍存在偏差。相关论文于2024年11月4日发表在《自然—遗传学》杂志上。

据悉，近来几乎所有的阿尔茨海默病（AD）全基因组关联研究（GWAS）都进行了荟萃分析，将AD临床诊断研究，与基于亲本病史的主题代理表型研究结合起来。

研究人员报告了目前GWAS-by-proxy （GWAX）实践的主要局限性，由于未纠正的生存偏差和父母疾病调查的非随机参与，这导致了AD GWAS和GWAX结果之间的巨大差异。

研究人员证明，目前的AD GWAX提供了AD风险与高等教育之间高度误导的遗传相关性，影响了涉及AD和认知的各种遗传流行病学应用。他们的研究揭示了中年生物库队列设计和分析中的潜在问题，并强调，在解释基于代理报告的亲代病史的遗传关联结果时需要谨慎。

附：英文原文

Title: Pervasive biases in proxy genome-wide association studies based on parental history of Alzheimer’s disease

Author: Wu, Yuchang, Sun, Zhongxuan, Zheng, Qinwen, Miao, Jiacheng, Dorn, Stephen, Mukherjee, Shubhabrata, Fletcher, Jason M., Lu, Qiongshi

Issue&Volume: 2024-11-04

Abstract: Almost every recent Alzheimer’s disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and nonrandom participation in parental illness surveys, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that the current AD GWAX provide highly misleading genetic correlations between AD risk and higher education, which subsequently affects a variety of genetic epidemiological applications involving AD and cognition. Our study sheds light on potential issues in the design and analysis of middle-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

DOI: 10.1038/s41588-024-01963-9

Source: https://www.nature.com/articles/s41588-024-01963-9